Handbook of
`PHARMACEUTICAL
`EXCIPIENTS
`
`Third Edition
`
`Edited by
`Arthur H. Kibbe, Ph.D.
`Professor and Chair
`Department of Pharmaceutical Sciences
`Wilkes University School of Pharmacy
`Wilkes-Barre, Pennsylvania
`
`American Pharmaceutical Association
`Washington, D.C.
`
`(RP)
`
`Phannaceutical Press
`London, United Kingdom
`
`KASHIV1047
`IPR of Patent No. 9,492,392
`
`

`

`Published by the American Pharmaceutical Association
`2215 Constitution Avenue NW, Washington, DC 20037-2985, USA
`www.aphanet.org
`and the Pharmaceutical Press
`1 Lambeth High Street, London SEl 7JN, UK
`www.pharmpress.com
`
`© 1986, 1994, 2000 American Pharmaceutical Association and Pharmaceutical Press
`
`First edition 1986
`Second edition 1994
`Third edition 2000
`
`Printed in the United States of America
`
`ISBN: 0-85369-381-1 (UK)
`ISBN: 0-917330-96-X (USA)
`
`Library of Congress Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients I edited by Arthur H. Kibbe.--3rd ed.
`p.; em.
`Includes bibliographical references and index.
`ISBN 0-917330-96-X
`1. Excipients--Handbooks, manuals, etc.
`Pharmaceutical Association.
`[DNLM: 1. Excipients--Handbooks. QV 735 H236 2000]
`RS20l.E87 H36 2000
`615'.19--dc21
`
`I. Kibbe, Arthur H. II. American
`
`A catalogue record for this book is available from the British Library.
`
`99-044554
`
`All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or
`by any means, without the prior written permission of the copyright holder. The publisher makes no representation, express or
`implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or
`liability for any errors or omissions that may be made.
`
`Managing Editor:
`Copy editor:
`Indexer:
`Compositor:
`Cover Designer:
`
`Melanie Segala
`Paul Gottehrer
`Lillian Rodberg
`Roy Barnhill
`Tim Kaage
`
`KASHIV1047
`IPR of Patent No. 9,492,392
`
`

`

`Polyethylene Oxide
`
`1. Nonproprietary Names
`USP: Polyethylene oxide
`
`2. Synonyms
`Polyox; polyoxirane; polyoxyethylene.
`
`3. Chemical Name and CAS Registry Number
`Polyethylene oxide [25322-68-3]
`
`4. Empirical Formula
`See. Table I.
`
`Molecular Weight
`
`5. Structural Formula
`(CH2CH20)n
`Polyethylene oxide is a nonionic homopolymer of ethylene oxide,
`where n represents the average number of oxyethylene groups (about
`2000 to over 100 000). It may contain up to 3% of silicon dioxide.
`
`6. Functional Category
`Hydrophilic matrix formation; mucoadhesive; tablet binder;
`thickening agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Polyethylene oxide can be used as a tablet binder at concen-
`trations from 5-85%. The higher molecular weight grades pro-
`vide delayed drug release via the hydrophilic matrix approach.
`Fig. 1 presents the relationship between swelling capacity and mo-
`lecular weight which is a good guide when selecting products for
`use in immediate- or sustained-release matrix formulations.
`Polyethylene oxide has been shown to be an excellent mucoad-
`hesive polymer.(l) Low levels of polyethylene oxide are effective
`thickeners, although alcohol is usually added to water-based for-
`mulations to provide improved viscosity stability. Polyethylene
`
`h .... ""
`':-•-- ---------------
`
`..
`
`........................ ..
`900,000 •••••
`
`200,000
`0'~o~·~···-·•~·~--~~-~---1Lo _____ 1L5 _____ 2Lo~--~25----~so
`
`Time (hours)
`
`Fig. 1: Swelling capacity of polyethylene oxide (J'olyox WSR).
`Measured for four molecular weight grades; 28 mm tablets in
`300 mL of water.
`
`Polyethylene Oxide 399
`
`oxide films demonstrate good lubricity when wet. This property
`has been utilized in the development of coatings for medical de-
`vices. Polyethylene oxide can be radiation crosslinked in solution
`to produce a hydrogel. The hydrogels so produced have been used
`in wound-care applications.
`
`Table I: Number of repeat units and molecular weight as a function
`of polymer grade.
`Approximate number Approximate molecular
`of repeating units
`weight
`2275
`100 000
`4500
`200 000
`6800
`300 000
`9100
`400 000
`14 000
`600 000
`20000
`900 000
`23 000
`1 000 000
`45 000
`2 000 000
`90 000
`4 000 000
`114000
`5 000 000
`159 000
`7 000 000
`
`Polyox grade
`WSRN-10
`WSRN-80
`WSR N-750
`WSRN-3000
`WSR 205
`WSR 1105
`WSRN-12K
`WSRN-60K
`WSR 301
`WSR Coagulant
`WSR 303
`
`Note: Molecular weight based on dilute viscosity measurements.
`
`Table II: Polyethylene oxide viscosity at 25°C (mPa s).
`Polyox grade
`5% solution
`1% solution
`2% solution
`WSRN-10
`30-50
`WSRN-80
`65-115
`WSRN-750
`600-1200
`WSRN3000
`2250-4500
`WSR205
`4500-8800
`WSR 1105
`8800-17 600
`WSRN-12K
`WSRN-60K
`WSR 301
`WSR coagulant
`WSR 303
`
`1500-5500
`5500-7500
`7500-10 000
`
`400-800
`2000-4000
`
`Note: All· solution concentrations are based on the water content of the
`hydro-alcoholic solutions.
`
`8. Description
`White to off-white, free-flowing powder. Slight ammoniacal odor.
`
`9. Pharm~copeial Specifications
`
`Test
`Identification
`Loss on drying (105°C for 45 min)
`N onsilicon dioxide loss on ignition
`Silicon dioxide
`Heavy metals
`Free ethylene oxide
`Organic volatile impurities
`Trichloroethylene
`Viscosity
`
`USP
`+
`s;I%
`s; 2%
`s;3%
`s; 0.001%
`s; 10 ppm
`+
`s;roo ppm
`+
`
`10. Typical Properties
`Angle of repose: 34°
`Density (true): 1.3 glee
`Melting point: 65-70°C
`Moisture content: < 1%. See also Fig. 2.
`
`KASHIV1047
`IPR of Patent No. 9,492,392
`
`

`

`400 Polyethylene Oxide
`
`25r---------------------------------·
`
`20
`
`5
`
`20
`
`40
`Relative humidity(%)
`
`100
`
`Fig. 2: Moisture sorption isotherm for polyethylene oxide
`(Polyox WSR), (Union Carbide Corp.)
`
`Solubility: polyethylene oxide is soluble in water and a num-
`ber of common organic solvents such as acetonitrile, chlo-
`roform, and methylene chloride. It is insoluble in aliphatic
`hydrocarbons, ethylene glycol, and most alcohols. <2l
`
`11. Stability and Storage Conditions
`Store in tightly sealed containers in a cool, dry, place. Avoid
`exposure to high temperatures since this can result in viscosity
`reduction.
`
`12. Incompatibilities
`Polyethylene oxide is incompatable with strong oxidizing
`agents.
`
`13. Method of Manufacture
`Prepared by the polymerization of ethylene oxide using a suit-
`able catalyst. <2l
`
`14. Safety
`Animal studies suggest that polyethylene oxide has a low level
`of toxicity regardless of the route of administration. It is poor-
`ly absorbed from the gastrointestinal tract but appears to be
`completely and rapidly eliminated. The resins are neither skin
`irritants nor sensitizers, nor do they cause eye irritation. (6)
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled.
`
`16. Regulatory Status
`Included in the FDA Inactive Ingredients Guide (sustained-
`release tablets).
`
`Fig. 3: SEM of polyethylene oxide (Polyox WSR), (Union Carbide
`Corp.). Magnifications at lOOX (top) and 300X (bottom).
`
`18. Related Substances
`Polyethylene glycol.
`
`19. Comments
`
`20. Specific References
`1. Bottenberg P, et al. Development and testing bioadhesive.
`J Pharm Pharmacal 1991; 43: 457-464.
`2. Bailey FE Jr., Kolesky JV. Poly( ethylene oxide). London, Aca-
`demic Press, 197 6.
`
`21. General References
`Union Carbide Corp. Technical Literature: Polyox water soluble
`resin, 1998.
`Yu DM, Amidon GL, Weiner ND, Goldberg AH. Viscoelastic
`properties of poly( ethylene oxide) solution. J Pharm Sci 1994;
`83: 1443-1449
`
`17. Pharmacopeias
`us.
`
`22. Author
`RL Schmitt.
`
`KASHIV1047
`IPR of Patent No. 9,492,392
`
`

`

`HFC 152a, 184
`HFC (ditluoroethane), 184
`High fructose syrup, 211
`HMCP, 256
`Hodag GMO, 223
`Hodag GMS, 225
`Hodag PEG, 392
`Hodag SML, 511
`Hodag SMO, 511
`Hodag SMP, 511
`Hodag SMS, 511
`Hodag SSO, 511
`Hodag STS, 511
`Hog gum (caramania), 569
`Homopolymer ethenol, 424
`Homopolymer 1-ethenyl-2-pyrrolidinone, 433
`HPMC, 252
`HSA, 5
`Human serum albumin, 5
`Human serum albumin, normal, 5
`Humectants
`.
`glycerin, 220
`propylene glycol, 442
`sorbitol, 515
`triacetin, 570
`Hyamine 3500, 33
`Hydrated aluminum silicate, 269
`Hydrate sodium propanoate, 498
`Hydrate sodium propionate, 498
`Hydrate sodium salt, 498
`Hydrocarbons (HC), 236
`Hydrochloric acid, 239
`Hydrogenated
`castor oil, 92, 579
`cottonseed oil, 578
`glucose syrup, 315
`maltose, 313
`oil, 578
`palm oil, 578
`polyoxyl castor oil, 412
`soybean oil, 578
`vegetable glycerides, 550
`vegetable oil
`type I, 157, 578
`type IT, 579
`Hydrogen 1,2-benzenedicarboxylate
`2-hydroxypropyl methyl ether, 256
`Hydrogen 1,2-benzenedicarboxylate, 99
`Hydrogen carbonate, 476
`Hydrogen orthophosphate, dipotassium, 494
`Hydrogen phosphate, disodium, 493
`Hydrogen sulfite, 491
`a.-Hydro-ro-hydroxy-poly( oxy-1,2-
`ethanediy 1), 392
`a.-Hydro-ro-
`hydroxypoly( oxyethylene )poly( oxy
`propylene )poly( oxyethylene) block
`copolymer, 386
`2-Hydropertluoropropane, 234
`Hydrophilic matrix formation
`polyethylene oxide, 399
`Hydrous lanolin, 287, 289, 290
`Hydrous wool fat, 290
`Hydroxyapatite, 68
`Hydroxybenzene, 367
`4-Hydroxybenzoic acid butyl ester, 53
`
`4-Hydroxybenzoic acid ester, 340
`4-Hydroxybenzoic acid ethyl ester, 205
`4-Hydroxybenzoic acid propyl ester, 450
`Hydroxybutanedioic acid, 311
`2-Hydroxy-1,4-butanedioic acid, 311
`(RS)-(±)-Hydroxybutaneioic, 311
`1-Hydroxy-1,2-ethanecarboxylic acid, 311
`4-Hydroxy-3-ethoxybenzaldehyde, 208
`~-Hydroxyethylamine, 350
`2-Hydroxyethylamine, 350
`~-Hydroxyethyl benzene, 372
`Hydroxyethyl cellulose, 240, 248, 254
`Hydroxyethylcellulosum, 240
`2-Hydroxyethyl-~-cyclodextrin, 167
`Hydroxyethyl ether, 240
`2-Hydroxyethyl ether, 240
`~-Hydroxyethyl phenyl alcohol, 370
`~-Hydroxyethyl phenyl ether, 370
`3-Hydroxy-2-ethyl-4-pyrone, 201
`4-Hydroxy-m-anisaldehyde, 576
`4-Hydroxy-2-methoxybenzaldehyde, 576
`3-Hydroxy-2-methyl-4H-pyran-4-one, 320
`N-(Hydroxymethyl)-N-(1,3-dihydroxymethy 1-
`2,5-dioxo-4-imidazolidinyl)-N'-
`(hydroxymethyl)urea, 262
`3-Hydroxy-2-methyl-(1,\1.-pyran), 320
`3-Hydroxy-2-methyl-4-pyrone, 320
`p-Hydroxy-m-methoxybenzaldehyde, 576
`1-Hydroxy-2-phenoxyethane, 370
`2-Hydroxy-1,2,3-propanetricarboxylic acid,
`triethyl ester, 573
`2-Hydroxypropane-1,2,3-tricarboxylic acid
`monohydrate, 140
`2-Hydroxy-1,2,3-propanetricarboxylic acid
`tripotassium salt monohydrate,
`429
`2-Hydroxy-1,2,3-propanetricarboxylic acid
`monohydrate, 140
`1-Hydroxypropanol, 442
`a.-Hydroxypropionic acid, 272
`2-Hydroxypropionic acid, 272
`(R)-(-)-2-Hydroxypropionic acid, 272
`(S)-(+)-2-Hydroxypropionic acid, 272
`Hydroxypropyl alginate, 445
`Hydroxypropyl cellulose, 243, 244, 250, 254
`low-substituted, 248, 249
`Hydroxypropylcellulosum, 244
`2-Hydroxypropyl-~-cyclodextrin, 167
`3-Hydroxypropyl-~-cyclodextrin, 167
`Hydroxypropyl ether, 244
`2-Hydroxypropyl ether, 244
`low-substituted, 249
`Hydroxypropyl methylcellulose, 243, 248, 252,
`259, 338
`Hydroxypropyl methylcellulose phthalate, 100,
`254, 256
`2-Hydroxypropyl methylcellulose phthalate,
`256
`Hydroxypropyl methyl ether, 252
`2-Hydroxypropyl methyl ether, 252
`2-Hydroxysuccinic acid, 311
`Hydroxytoluene, 50, 158
`Hy-Phi, 356
`Hyprolose, 244
`HyQual, 608
`Hystrene, 534
`
`Index 655
`
`Icing sugar, 546
`Idroramnosan, 240
`Imidazolidinyl urea, 261
`Irnidurea, 261
`2,2' -lminobisethanol, 180
`2,2'-Iminodiethanol, 180
`Imwitor 191, 225
`Imwitor 900K, 225
`lndanthrene blue (D&C blue #9), 147
`Indices
`Bonding Index (BI), 637
`Brittle Fracture Index (BFI), 637
`Indigo carmine, 146, 151
`Indigotine (FD&C blue #2), 147
`Indigotine (FD&C blue #4 lake), 148
`Industrene, 356, 534
`Industrial methylated spirit, 8
`Instastarch, 528
`Instrumentation, 636
`Invert sugar, 543
`IPA, 263
`Irish moss extract, 91
`Iron oxide coloring agents, 146, 148, 150, 151
`Iro~ oxides, synthetic, 149
`Isceon 134a, 560
`Isceon 142b, 132
`Isobutane, 236
`Isomyst, 265
`6-Isooctadecanoate, 511
`Isopal, 267
`Isopalm, 267
`Isopropanol, 263
`Isopropyl alcohol, 8, 263
`Isopropyl hexadecanoate, 267
`Isopropy lis myristas, 265
`Isopropylis palmitas, 267
`2-I~opropyl-5-methylcyclohexanol, 334
`4-Isopropyl-1-methylcyclohexan-3-ol, 334
`Isopropyl myristate, 265, 268
`Isopropyl palmitate, 266, 267
`Isotron, 134
`
`fa-Fa !PM, 265
`fa-Fa IPP, 267
`Jaguar gum, 232
`Jelly
`mineral, 362
`petroleum, 362
`yellow petroleum, 362
`Jinjili oil, 460
`
`Kalii chloridum, 426
`Kalii citras, 429
`Kalii hydrogencarbonas, 476
`Kalii sorbas, 431
`Kaolin, 32, 269, 298
`Kaolinum ponderosum, 269
`Kelacid, 10
`Kelcoloid, 445
`Keltone, 465
`Kelcosol, 465
`Keltrol, 599
`Kems~rene, 220
`Keotlo ADP, 531
`Kessco 40, 225
`Kessco EO, 203
`
`KASHIV1047
`IPR of Patent No. 9,492,392
`
`